Inheritance Patterns

Abstract: Medical genetics was revolutionized during the 1980s by the application of genetic mapping to locate the genes responsible for simple Mendelian diseases. Most diseases and traits, however, do not follow simple inheritance patterns. Geneticists have thus begun taking up the even greater challenge of the genetic dissection of complex traits. Four major approaches have been developed: linkage analysis, allele-sharing methods, association studies, and polygenic analysis of experimental crosses. This article synthesizes the current state of the genetic dissection of complex traits—describing the methods, limitations, and recent applications to biological problems.

Abstract: This review describes new developments in the study of transgenerational epigenetic inheritance, a component of epigenetics. We start by examining the basic concepts of the field and the mechanisms that underlie epigenetic inheritance. We present a comprehensive review of transgenerational cellular epigenetic inheritance among different taxa in the form of a table, and discuss the data contained therein. The analysis of these data shows that epigenetic inheritance is ubiquitous and suggests lines of research that go beyond present approaches to the subject. We conclude by exploring some of the consequences of epigenetic inheritance for the study of evolution, while also pointing to the importance of recognizing and understanding epigenetic inheritance for practical and theoretical issues in biology.

Abstract: Double-stranded RNA interference (RNAi) in Caenorhabditis elegans is heritable; here a genetic screen for factors required for RNAi inheritance identifies the nuclear-localized Argonaute gene hrde-1, which acts in the germ cells of progeny to promote multigenerational inheritance of silencing and, also, germline immortality. Gene silencing due to RNA-mediated interference (RNAi) in the nematode Caenorhabditis elegans can be inherited for more than five generations. Here, Scott Kennedy and colleagues have performed a genetic screen for defects in the transmission of RNAi-silencing signals to future generations, and identify a nuclear-localized Argonaute protein termed HRDE-1. It associates with small-interfering RNAs and acts in the germ cells of the progeny of animals exposed to double-stranded RNA to promote multigenerational inheritance of silencing. The authors propose that one biological function of the RNAi-inheritance machinery is to transmit ‘germline immortality’ in the form of small RNAs, selected for their ability to promote fertility, across generational boundaries. Epigenetic information is frequently erased near the start of each new generation1. In some cases, however, epigenetic information can be transmitted from parent to progeny (multigenerational epigenetic inheritance)2. A particularly notable example of this type of epigenetic inheritance is double-stranded RNA-mediated gene silencing in Caenorhabditis elegans. This RNA-mediated interference (RNAi) can be inherited for more than five generations3,4,5,6,7,8. To understand this process, here we conduct a genetic screen for nematodes defective in transmitting RNAi silencing signals to future generations. This screen identified the heritable RNAi defective 1 (hrde-1) gene. hrde-1 encodes an Argonaute protein that associates with small interfering RNAs in the germ cells of progeny of animals exposed to double-stranded RNA. In the nuclei of these germ cells, HRDE-1 engages the nuclear RNAi defective pathway to direct the trimethylation of histone H3 at Lys 9 (H3K9me3) at RNAi-targeted genomic loci and promote RNAi inheritance. Under normal growth conditions, HRDE-1 associates with endogenously expressed short interfering RNAs, which direct nuclear gene silencing in germ cells. In hrde-1- or nuclear RNAi-deficient animals, germline silencing is lost over generational time. Concurrently, these animals exhibit steadily worsening defects in gamete formation and function that ultimately lead to sterility. These results establish that the Argonaute protein HRDE-1 directs gene-silencing events in germ-cell nuclei that drive multigenerational RNAi inheritance and promote immortality of the germ-cell lineage. We propose that C. elegans use the RNAi inheritance machinery to transmit epigenetic information, accrued by past generations, into future generations to regulate important biological processes.

Abstract: Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.